title: Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation.
abstract: BRAF is an oncogenic protein kinase that drives cell growth and proliferation through the MEK-ERK signaling pathway. BRAF inhibitors have demonstrated antitumor efficacy in melanoma therapy but have also been found to be associated with the development of cutaneous squamous cell carcinomas (cSCCs) in certain patients. Here, we report that BRAF is phosphorylated at Ser729 by AMP-activated protein kinase (AMPK), a critical energy sensor. This phosphorylation promotes the association of BRAF with 14-3-3 proteins and disrupts its interaction with the KSR1 scaffolding protein, leading to attenuation of the MEK-ERK signaling. We also show that phosphorylation of BRAF by AMPK impairs keratinocyte cell proliferation and cell-cycle progression. Furthermore, AMPK activation attenuates BRAF inhibitor-induced ERK hyperactivation in keratinocytes and epidermal hyperplasia in mouse skin. Our findings reveal a mechanism for regulating BRAF signaling in response to energy stress and suggest a strategy for preventing the development of cSCCs associated with BRAF-targeted therapy.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA; Department of Dermatology, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Che-Hung
authors.initials: CH
authors.lastname: Shen
authors.forename: Ping
authors.initials: P
authors.lastname: Yuan
authors.forename: Rolando
authors.initials: R
authors.lastname: Perez-Lorenzo
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sze Xian
authors.initials: SX
authors.lastname: Lee
authors.forename: Yang
authors.initials: Y
authors.lastname: Ou
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D012694:Serine; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases